Venous and lymphatic malformations (VMs and LMs) are congenital birth defects that occur as a result of somatic mutations in the PIK3CA gene. These lesions often present in the extremities, involve the dermis, and may worsen over time with symptoms including exudence, severe pain, limb distortion and functional impairment. They are currently treated with either sclerotherapy or surgical procedures, which have limited effect and are painful and disruptive to quality of life. Thus, there is an urgent and unmet need for the development of an alternative treatment via medication. Phosphoinositide 3-kinases (PI3Ks) are enzymes encoded by PIK3CA and play roles in cell growth, proliferation, differentiation, motility, survival and intracellular trafficking. PIK3CA mutations have been identified in VMs and LMs. Therefore, the inhibition of PI3K pathway presented a viable therapeutic target that may potentially provide an effective treatment for VMs and LMs. Because of the nature of these disorders, it may be desirable to deliver such a treatment topically rather than orally. Many compounds represented generally by formula I display excellent PI3K inhibition activities and may be useful against cancer cell growth. Venthera has developed representative compounds of this series for topical delivery medication to treat VMs and LMs. However, further development efforts led to the design and preparation of several successful formulations that enhanced the skin permeation and improved phys. properties to achieve better topical delivery. This presentation will highlight the progress on the development of new medication with suitable formulations aiming to provide a new topical treatment for VMs and LMs.